Basic Principles of Cancer Immunotherapy Elizabeth Budde, MD, PhD City of Hope Disclosures • No relevant financial relationships to disclose • I will be discussing non-FDA approved indications during my presentation. Why does the immune system fail to eliminate cancer?
Cancer cells grow progressively in immunocompetent hosts without evidence of T cell exhaustion or systemic anergy. The 3 Es of cancer immunoediting The 3 Es of cancer immunoediting The 3 Es of cancer immunoediting The 3 Es of cancer immunoediting
Multi-layered immunosuppression
• Tumors insulate themselves with dense layers of immunosuppressive stroma • Overcoming the many layers of interconnected and often functionally redundant immune suppressive mechanisms represents a daunting challenge for tumor- specific T cells • Immunotherapy can “peel back” the layers of local immune suppression, thereby restoring the capacity of T cells to eradicate the tumor Types of immunotherapy Three signals for antigen-specific T cell activation T cell checkpoint modulation CTLA-4, a negative regulator of T cell activity limits the responsiveness of activated T cells Anti-CTLA-4 induces regression of transplantable colon carcinoma Ipilimumab (human anti-CTLA-4) was approved for the treatment of metastatic melanoma by FDA in 2010 Which T cells are affected by ipilimumab (aCTLA-4)?
The efficacy and selectivity of anti-CTLA-4 therapy increase in patients who have higher percentages of activated tumor-specific T cells at the time of treatment PD-1: PD-L1 inhibitory pathway
Therapeutic cancer vaccines Components of a cancer vaccine
Mode of Administration An intra-nasal HPV E6/E7: a-GalCer vaccine slows growth of TC-1 tumors 4-1BB agonist antibody and HPV E6/E7 vaccine synergize in curing TC-1 tumors Intratumoral injection of innate immune agonists: The direct vaccination approach
Corrales L and Gajewski TF
Adoptive T cell therapy can involve engineered (CAR, TCAR) or patient-derived (TIL, PBMC) T cells T cell adoptive transfer
CARs, TIL, TCR, PBMCs Effective treatment of relapsed B cell ALL with CD19 CAR T cell therapy
Effector antibodies and antibody-drug conjugates (ADCs)
Radiolabeled or Key ADC / antibody principles SGN-70A in the clinic for NHL and RCC
Jeffrey SC et al. 2013. Bioconjug Chem. 24(7): 1256-63
Immune recognition of tumor and Augmentation of Removal of barriers to mobilization of anti- tumor-specific T cells immune rejection tumor effectors
• Vaccines • Co-inhibitory blockade • Tumor vascular resistance • Chemotherapy • Co-stimulatory activation • Desmoplastic stroma • Radiation • Activation of APCs • Hypoxic microenvironments • ACT (CARs, TCR transfer) • Innate immune recognition A different perspective on chemotherapy Immunogenic versus non-immunogenic cell death A different perspective on chemotherapy Immunogenic versus non-immunogenic cell death Radiation Therapy: A potent adjuvant for tumor immunity Abscopal effect
• Localized treatment of a tumor causes/evokes reduction of distant ones • Immunotherapy + radiotherapy with targeted immunomodulators and immune checkpoint blockade is intended to elicit the abscopal effect. Radiotherapy synergizes with blockade of CTLA-4 and PD-1 to cure melanoma lung metastases Why combination immunotherapy is the future? More consistent benefit for a larger percentage of patients with a wide range of cancer types